AU8441198A - Beta-alkoxyacrylates against malaria - Google Patents

Beta-alkoxyacrylates against malaria Download PDF

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Publication number
AU8441198A
AU8441198A AU84411/98A AU8441198A AU8441198A AU 8441198 A AU8441198 A AU 8441198A AU 84411/98 A AU84411/98 A AU 84411/98A AU 8441198 A AU8441198 A AU 8441198A AU 8441198 A AU8441198 A AU 8441198A
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Australia
Prior art keywords
phenyl
compounds
optionally substituted
lower alkyl
halogen
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AU84411/98A
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AU748990B2 (en
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Jawad Alzeer
Jacques Chollet
Christian Hubschwerlen
Hugues Matile
Robert George Ridley
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The present invention relates to compounds having the formulae wherein R, R1, R6, R7, Rn8, X, and Z are defined herein, which are useful in the treatment or prophylaxis of malaria. The compounds of the present invention are especially useful in the treatment or prophylaxis of chloroquine-sensitive and chloroquine-resistant malaria.

Description

WO 99/02150 PCT/EP98/04162 -1 D-Alkoxvacrylates against malaria The invention relates to compounds of the general formulae
OR
R 1 O R ' R O X10 X RO O R 6 R or Z IA
R
7 R IB wherein 5 R 1 is lower alkyl X is N or CH A' R in IA is Y lal wherein Y is S or O and 10 A 1 is phenyl, which may be substituted by one or more substituents, selected from halogen, lower alkoxy, lower alkyl, CF 3 , NO 2 , NH 2 , phenoxy or CFa phenoxy; naphthyl; isothiazol-3-yl; thiazol-2-yl, optionally substituted by lower alkoxyalkoxyalkyl, 15 lower alkyl, lower alkoxycarbonyl or lower acetoxyalkyl; thiadiazol-2-yl, optionally substituted by lower alkylthio, lower alkinylthio, cycloalkyl alkylthio, CF 3 or -NHC 6
H
4
CF
3 ; quinoxalin-2-yl, optionally substituted by halogen or lower alkyl; 20 benzoxazol-2-yl; benzotriazine, optionally substituted by an oxo-group; and quinolin-2-yl; 0 - Nr-A 2 or R2 Ia2 wherein WO 99/02150 PCT/EP98/04162 -2
R
2 is hydrogen, lower alkoxycarbonyl, CF 3 , lower alkyl, cycloalkyl, lower alkoxyalkyl, lower alkylthioalkyl or lower alkoxy and
A
2 is phenyl, which may be substituted by one or 5 more substituents, selected from lower alkyl, CF 3 , halogen, lower alkylthio, lower alkoxy or NO 2 ; -C(0)C 6
H
5 ; -C(CH 3
)=CH-C
6
H
4 -lower alkyl;
-CH=CH-C
6
H
5 ; pyridin-2-yl; pyridin-3-yl; pyridin 4-yl; thiazol-5-yl, optionally substituted by lower 10 alkyl; thien-3-yl, optionally substituted by lower alkyl; thien-2-yl, optionally substituted by halogen; quinolin-2-yl; naphthyl, benzo[b]thiophen-2-yl, optionally substituted by lower alkyl or halogen; or benzo[blfuran-2-yl;
R
3 15 or W A Ia3 wherein W is S, O, NH or CH 2 ;
R
3 is hydrogen or lower alkyl and
A
3 is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H 20 pyran or phenyl, which may be substituted by one or more substituents, selected from halogen, CF 3 or lower alkyl; or Ia4 wherein 25 A 4 is phenyl, which may be substituted by one or more substituents, selected from NO 2 , lower alkoxy, halogen, CF 3 ,phenyloxy, styryl-phenyl or (2-CF 3 - or Cl-phenyl)-furan-2-yl; benzo[1,3]dioxol 5-yl, optionally substituted by halogen; isoxazol-4 30 yl, optionally substituted by phenyl or lower alkoxyalkoxy; quinolin-3-yl; pyridin-2-yl; pyridin 3-yl, pyridin-4-yl; furyl; thien-2-yl; thien-3-yl;
-C-C-C(CH
3
)
3 ; -C=C-C 6
H
5 ; indolizin-2-yl, optionally substituted by lower alkyl; benzofuran- WO 99/02150 PCT/EP98/04162 -3 2-yl; benzopyran-3-yl or dihydrobenzo[bithiophen 5 -yl;
R
4 or A Ia5 wherein 5 R 4 is hydrogen or lower alkyl; and
A
5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO 2 , halogen, cyano or CF 3 ; pyridin-2-yl; pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl; 10 pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower alkyl; thiazol-2-yl, optionally substituted by C 6
H
4 Cl; thiazol-4-yl, optionally substituted by phenyl; 15 benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo[blthiophen-3-yl; or I a6 wherein
A
6 is phenyl, optionally substituted by CF 3 ; 20 or A 7 la7 wherein
A
7 is phenyl, optionally substituted by CF 3 ; or -(CH 2 )n-A 8 Ia8 wherein 25 n is 4 and
A
8 is phenyl, which may be substituted by one or more substituents, selected from CF 3 , halogen or
-CH=N-OCH
2
-CO-OCH
3 ; naphthyl or pyridin-4-yl; S or
A
9 Ia9 or 30 wherein
A
9 is phenyl, optionally substituted by CF 3 ; and wherein in formula IB
R
6
-R
8 are hydrogen, lower alkyl or lower alkoxy and WO 99/02150 PCT/EP98/04162 -4 Z is hydrogen; lower alkoxy; lower alkyl; or halogen or ' 1b wherein V is O, -N(CH 3 )-, -S- and 5 B 1 is phenyl, optionally substituted by halogen or alkyl; quinolin-8-yl; pyrimidin-2-yl; -CH(CH3) C6H5; or -CH 2
-C
6
H
5 ; O O1 (CH)m B 2 or O (CH)m 1b2 wherein 10 m is 0 or 1; and
B
2 is phenyl, optionally substituted by halogen, lower alkyl or CF 3 ; or benzo[b]thiophen-5-yl; O or '<0 ' B3 Ib3 wherein 15 B 3 is phenyl, optionally substituted by CF 3 ; 1ON
B
4 or R5 Ib4 wherein
R
5 is hydrogen, lower alkyl or lower alkoxyalkyl and
B
4 is phenyl, optionally substituted by CF 3 ; pyridin 20 2-yl; or thiazolin-5-yl, optionally substituted by lower alkyl; or - B 5 b5 wherein
B
5 is phenyl; -C-C-C(CH 3
)
3 ; or thien-3-yl; 25 as well as pharmaceutically acceptable salts of compounds of formulae IA and IB. All possible stereoisomers as well as their racemates are included in formulae IA and IB. It has now surprisingly been found that compounds of the present invention are useful against malaria. Every year, between 300 and 500 30 million people develop malaria. Close to 3 million people die as a result WO 99/02150 PCT/EP98/04162 -5 of this disease, most of them children and nearly all of them living in tropical Africa. Fifty years ago, many people thought that malaria could be completely eradicated. But over the past twenty years, malaria has been making a comeback. For years, chloroquine has been the standard 5 treatment, but in some areas the malaria parasite is resistant to chloro quine and to cocktails of almost all the older antimalarials. Around 40% of the world's population now live in areas where malaria is found. The compounds of the invention have the property that they are active not only against chloroquine-sensitive, but also against 10 chloroquine-resistant malaria pathogens. For this reason they are very well suited for the prophylaxis and treatment of malaria, especially in cases where the malaria pathogens are resistant to chloroquine. Most of the above described P-alkoxyacrylates and their salts are known compounds. They are described in the following documents EP 15 379 098, EP 299 694, WO 9007493, EP 278 595, EP 463 488, EP 370 629, EP 475 158, EP 474 042, EP 178 826, DE 3 519 280, EP 433 233, EP 460 575 and EP 254 426 as compounds with fungicidal activity for use in agriculture. The following compounds of formula IA5 are novel: oR 1 R1 X 0 0 R 4
A
s 20 IA5 wherein
R
1 is lower alkyl, X is N or CH,
R
4 is hydrogen or lower alkyl and 25 A 5 is phenyl, which may unsubstituted or substituted by one or more substituents, selected from lower alkyl, lower alkoxy,
NO
2 , halogen, cyano or CF 3 ; pyridin-2-yl; pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl; 30 thien-3-yl, optionally substituted by halogen and lower WO 99/02150 PCT/EP98/04162 -6 alkyl; thiazol-2-yl, optionally substituted by C 6
H
4 Cl; thiazol-4-yl, optionally substituted by phenyl; benzol[b]thiophen-2-yl, optionally substituted by halogen; or benzo [b]thiophen-3-yl; 5 as well as their pharmaceutically acceptable salts. Objects of the present invention are the use of the mentioned compounds of formulae IA and IB and their pharmaceutically acceptable salts thereof against chloroquine-sensitive and chloroquine resistant malaria pathogens, the use of these compounds for 10 manufacture of corresponding medicaments, medicaments, containing these compounds and their salts as well as new compounds of formula IA5 per se. The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear 15 alone or in combination. As used herein, the term "lower alkyl" denotes a straight or branched-chain alkyl group containing from 1-4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t butyl and the like. 20 The term "halogen" denotes chlorine, iodine, fluorine or bromine. The term "lower alkoxy" denotes an alkyl group, as defined earlier which is attached via an oxygen atom. The term "cycloalkyl" denotes saturated cyclic hydrocarbon residues containing 3 to 6 carbon atoms. The present invention embraces all possible racemates and their 25 optical antipodes. Preferred compounds of formula IA are especially those of formula IA5,
R
1 0X 0 0 R 4 \N \. As 1 A5 WO 99/02150 PCTIEP98/04162 -7 in which R 1 is methyl, X is CH, R 4 is hydrogen and A 5 is phenyl, substituted by one or more substituents, selected from CF 3 , bromine, chlorine, methoxy, NO 2 or lower alkyl; or naphthyl or thienyl. Compounds of formula IA2
OR
1 ,RX S OIN
A
2 5 IA2 in which R 1 is methyl, X is CH, R 2 is hydrogen or lower alkyl and A 2 is phenyl, substituted by CF 3 , chloro, fluoro, methyl, t-butyl or SCH 3 are also preferred. Another group of preferred compounds is the following: Al I R 1 10 [IA I in which R 1 is methyl, X is CH, Y is O or S and A 1 is phenyl, optionally substituted by methyl, isopropyl, t-butyl, bromo, chloro, CF 3 or methoxy; naphthalenyl; or thiadiazolyl, optionally substituted by thiomethyl or propynylthiocyclopropyl. 15 The following intermediates which are used in the process for preparation of compounds of formulae IA4 show also a pharmaceutical activity against malaria pathogens: 0oCH 3
H
3 C00 1 O Br
II
WO 99/02150 PCTIEP98/04162 -8
H
3 C.,CH III and oICH3
H
3 C00 \- OH II IV The compounds of formulae IA and IB can be prepared as described in the documents cited above. 5 In addition, compounds of formulas IA1-IA9 and IB1-IB5, can be prepared in accordance with schemes 1-14. Scheme 1 OR X RO RX Br " - A + A1YH VI V IA1 wherein the substituents have the significances described above. Scheme 2 OR'
A
2
R
1 X V \ 0O 0 S R2,C=NOH N A 2 VII
R
2 IA2 10 WO 99/02150 PCTIEP98/04162 -9 wherein the substituents have the signifcances described above. Scheme 3 R X R 3 RX O R 3 0'- 0l1 0 0' R Br Sn OTHP r OTHP IX x Vi lTHP=tetrahydro-pyran .. R I O O R ,1 O R3 3 R"OIX O 3R R"O, 0 3 \W, A AWH Br Br \ OH IA3 XI wherein the substituents have the significances described above. Scheme 4
OR
1
O
' RXl
R
1 X O ( 0 ", O O A 4 II + A 4 CHO- I p OCH3
OCH
3 XIII IA4 5 wherein the substituents have the significances described above. Scheme 5 RO, R0 ROX1 0 R 4 XIII + As ZZ CHO N \ A 5 XIV IA5 wherein the substituents have the significances described above.
WO 99/02150 PCT/EP98/04162 - 10 Scheme 6 Br
A
6 CHO A 6 B 0--Br
A
6 Br A 6 XV XVI RO.. -RxRIO., R Ox R O, R XVI + 6 - H A'.
I& XVII IA6 wherein the substituents have the significances described above. Scheme 7 Rl Br O
A
7
B
r A . Br XVII R1 X O XVIII XIX \ A 7 IA7 5 wherein the substituents have the significances described above. Scheme 8 0 lRl R' RIx 0<R 0 0 \. \ \AS*o
A
8 IA8 xxwherein the substituents have the significance described above. wherein the substituents have the significances described above.
WO 99/02150 PCT/EP98/04162 - 11 OR Scheme 9 Rl R 1O R OX A9 00 H 2
SO
4 SA A Na2S XXI IA9 wherein the substituents have the significances described above. Scheme 10 OIR' O ,Rl R XI1 1 00 0 + B 1 VH -- RX
IB
1 S/ Br XXIII V / \ IBI XXII wherein the substituents have the significances described above. Scheme 11 O, R 1 XXII + B2- (CH 2 )m OH
B
2 0 (CH 2 )m xxly S /\ 5 IB2 wherein the substituents have the significances described above.
WO 99/02150 PCT/EP98/04162 - 12 Scheme 12 Ro R o R°" ° X 00 0 XXII + B 3 O O' B 3 0 XXV s /0 B IB3 wherein the substituents have the significances described above. Scheme 13 o-R
B
4 RO0 R' XXII + B OOH O XO N B4 XXVI S R 5 IB4 5 wherein the substituents have the significances described above. Scheme 14 0 0 R 0 0 R O + B 5 CHO R0 S / P\ XXVIII \ B 5 /ocH 3 S - OCH 3 XXVII IB5 wherein the substituents have the significances described above. The novel compounds of formula IA5 can be prepared in 10 accordance with scheme 5 and by Examples 164-206.
WO 99/02150 PCTIEP98/04162 - 13 As mentioned earlier, the -alkoxyacrylates of general formulae IA and IB in accordance with the invention and their pharmaceutically usable salts have valuable pharmaceutical properties. In particular, they have a very good activity against malaria 5 pathogens. Their activity is equally good against chloroquine-resistant strains of the pathogen as against chloroquine-sensitive strains. Accordingly, the present compounds can also be used for the prophylaxis and cure of malaria even in those cases where the pathogen does not respond to chloroquine. 10 In the following table are described the tested compounds: 0 1R' Y 'A' IA1 R1 X Y A 1 Expl.No.
CH
3 -CH S C C, 1 CI
CH
3 CH S F 2
CH
3 -CH S cI 3 Cl
CH
3 -CH S 4
CH
3 -CH S 5
CI
WO 99/02150 PCTIEP98/04162 - 14 CH 3 -CH S 6 ON,
CH
3 CH S 7
CH
3 -CH S CF3 8
NO
2
CH
3 CH S r 9
CH
3 CH S 10 CH3 CH SF 11 F F F
CH
3 CH S o" 12
CH
3 CH S 13
CH
3 CH S 14
CH
3 CH S 15
CF
3
CH
3 CH S ' CF3 16
CH
3 CH S 17
(CH
2 )2-0O-(CH 2
)
2
-OCH
3 WO 99/02150 PCT/EP98/04162 - 15
CH
3 CH S 18
CH
3 CH S s, 19 N
CH
3 CH S 20 N N
CH
3 CH S " CF 21 NN
CH
3 CH S /> N 22
CF
3
CH
3 CH S c 23 N PN
CH
3 CH S ">1 24 N O L Or
CH
3 CH S o 25 0
CH
3 CH S N26 CH3 CH o I 27 N 0
CH
3 CH O N 28
CH
3 CH 0 N B 29 CH3 CH O 30
CH
3 CH 0 MJ,'Q 30 WO 99/02150 PCT/EP98/04162 - 16
CH
3 CH 0 31
CH
3 CH 0 32
CH
3 CH 0 NS 33
CH
3 CH O .NL 34
CH
3 CH O0 35 Preferred compounds are also those of formula IAI wherein R I is methyl, X is CH, Y is S or O, A' is phenyl, which may be substituted by one or more substituents, selected from hal, lower alkoxy, lower alkyl, 5 CF 3 , NO 2 , NH 2 , phenoxy, or CF3-phenoxy. Such compounds can be prepared according to the procedure set in example 1 of EP 278595, like the following specific compounds:
(E)-
2 -[2-(2-Bromo-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester; o10 (E)-3-methoxy-2- [2-(4-phenoxy-phenoxymethyl)-phenyl]-acrylic acid methyl ester; (E)-3-methoxy-2-[2-[4-(4-trifluoromethyl-phenoxy)-phenoxy methyl]-phenyl]-acrylic acid methyl ester; (E)-3-methoxy-2-[2-(4-methoxy-2-nitro-phenoxymethyl)-phenyl] 15 acrylic acid methyl ester; (E)-2-[2-(2,4-dibromo-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
(E)-
2 -[2-(2-chloro-4-methyl-phenoxymethyl)-phenyl]-3-methoxy acrylic acid methyl ester; 20 (E)-2-[2-(2-chloro-4-trifluoromethyl-phenoxymethyl)-phenyl]-3 methoxy-acrylic acid methyl ester; (E)-3-methoxy-2-(2-pentafluorophenyloxymethyl-phenyl)-acrylic acid methyl ester; WO 99/02150 PCT/EP98/04162 - 17 (E)-2-[2-(2,4-dichloro-phenylsulfanylmethyl)-phenyl]-3-methoxy acrylic acid methyl ester;
(E)-
2
-[
2
-(
2 -amino-4-trifluoromethyl-phenylsulfanylmethyl) phenyl]-3-methoxy-acrylic acid methyl ester; 5 (E)-2-[ 2
-(
2 -amino-4-methoxy-phenoxymethyl)-phenyl]-3-methoxy acrylic acid methyl ester;
(E)-
2
-[
2 -(4-tert-butyl-2-chloro-phenoxymethyl)-phenyl]-3-methoxy acrylic acid methyl ester. 0 0 N / R2 10 I 2 A2
R
I X R 2
A
2 Expl.No.
CH
3 CH -C(O)OCH 3 36
CH
3 CH CF 3 CF 37
CH
3 CH CH 3 c1 38 cl
CH
3 CH -(CH 2
)
2
CH
3 C 39
CF
3
CH
3 CH -] CN 40 C C aCF 3
CH
3 CH -<] 41
NI
WO 99/02150 PCTIEP98/04162 - 18
CH
3 CH -CH 2
OCH
3 42
CH
3 CH CH 3 F43 CI.
CH
3 CH CH 3 CF 44 S
CH
3 CH H 45
CH
3 CH CH 2
CH
3 N 46
CH
3 CH CH 3 ? 47
CF
3
CH
3 CH CH 3 48
CH
3 CH CH 2
CH
3 c 49
CH
3 CH CH 2
CH
3 a F 50
CH
3 CH CH 2
CH
3 Br 51
CH
3 CH CH 3 52 CH3 CH CH3 s53 CH 3 CH CH 3 I 53 WO 99/02150 PCT/EP98/04162 - 19
CH
3 CH CH 3 CF3 54 F
CH
3 CH CH 3 F 55
CH
3 CH CH 3 F 56 F
CH
3 CH CH 2
CH
3 F 57 F
CH
3 CH CH 2
CH
3 58 F
CH
3 CH CH 2
CH
3 59
CH
3 CH CH 2
SCH
3 60
CH
3 CH CH 3 I 61
CH
3 CH H 62
CH
3 CH H 63
CH
3 CH H a 64 Br
CH
3 CH H NB 65
CH
3 CH H c 66 cI WO 99/02150 PCTIEP98/04162 - 20 CH 3 CH CH 2
CH
3 67
CH
3 CH H N02 68
CH
3 CH CH 3 69
CH
3 CH CH 3 70
CH
3 CH H 71 F F
CH
3 CH H F 72
CH
3 CH CH 3 CF3 73
CF
3
CH
3 CH CH 3 74 Br
CH
3 CH CH 3 N0 75
NO
2
CH
3 CH CH 3 76
CH
3 CH CH 3 c, 77 S
CH
3 CH CH 3 cH3 78
CH
3 CH CH 3 Ncl 79 WO 99/02150 PCT/EP98/04162 -21 CH 3 CH CH 3 c 80
CCH
3 CH CH 3 81
CH
3 CH CH 3 82
CH
3 CH CH 3 83
CH
3 CH CH 3 N 84 CH3 CH CH3 c 84
CH
3 CH CH 3 85
CH
3 CH CH 3 0 o 86
CH
3 CH H c 87 ,,ct
CH
3 CH CH 3 88
CH
3 CH CH 3 cl 89
CH
3 CH CH 2
CH
3 c 90
CH
3 CH (CH 2
)
2
CH
3 91
CH
3 CH -< 92
CH
3 CH CH 3 N 93 0
CH
3 CH CH 3 94 WO 99/02150 PCT/EP98/04162 - 22 CH 3 CH H CF3 95
CH
3 CH CF 3 96
CH
3 CH CH 3 N02o 97
CH
3 CH H 98
CH
3 CH H 99
CH
3 CH H 100
CH
3 CH CH 3 101
CH
3 CH H C C 102 CHa CH H 103
CH
3 CH CH 3 104
CH
3 CH CH 3 F 105
CF
3
CH
3 CH CH 3 F 106
CH
3 CH CH 3 F 107 F
CH
3 CH CH 3 4 108
F
WO 99/02150 PCT/EP98/04162 - 23 CH 3 CH CH 3 F 109 F
CH
3 N CH 3 N0 110
CF
3
CH
3 N CH 3 CF3 111
CF
3
CH
3 N CF 3 / 112
CH
3 N CH 3 No 113
CH
3 N CH 3 Br 114 Br
CH
3 N CH 3 o' 115
CH
3 N CH 3 cl 116
CH
3 N CH 3 117 WO 99/02150 PCT/EP98/04162 - 24 O R 1 SOX 0 R 3 z \ W ,A3 \ w IA3
R
1 X R 3 W A 3 Expl.No.
CH
3 CH H 2 S F118 F F F
CH
3 CH H 2 S 119
CH
3 CH H 2 S 120
CF
3
CH
3 CH H 2 S sCF3 121
CH
3 CH H 2 O0 122 CH3 CH H2 NH 123
CH
3 CH H 2 NH CF3 124
CH
3 CH CH 3
CH
2 125 Preferred compounds are also those of formula IA3 wherein R 1 is 5 methyl, X is CH-, R 3 is H 2 , W is S, O, A3 is phenyl, which may be substituted by one or more substituents, selected from hal, CF 3 , lower WO 99/02150 PCT/EP98/04162 - 25 alkyl or is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran. Such compounds can be prepared according to the procedure set out in example 118, like the following additional compounds: (E)-2-[2-[(E)-3-(5-Acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran 5 2 -yloxy)-propenyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(E)-3-(2-chloro-phenylsulfanyl)-propenyl]-phenyl]-3 methoxy-acrylic acid methyl ester,
(E)-
2 -[2-[(E)-3-(2-chloro-4-methyl-phenoxy)-propenyl]-phenyl]-3 methoxy-acrylic acid methyl ester, and 10 (E)-2-[2-[(E)-3-(2-chloro-4-trifluoromethyl-phenoxy)-propenyl] phenyl]-3-methoxy-acrylic acid methyl ester.
O.R
1 R' X \ A 4 IM IA4
R
1 X A 4 Expl.No.
CH
3 CH 0 / 126 0 E/E NO2
CH
3 CH 0 / 127 0 # E/Z
NO
2
CH
3 CH c1 128 N02 E/Z
CH
3 CH C1 129 NO2
E/E
WO 99/02150 PCT/EP98/04162 - 26 CH 3 CH cl 130 CI
CH
3 CH 131 N02 E/E
CH
3 CH o 132 No E/Z
CH
3 CH ) 133 CI
CH
3 CH 134 -Cl Cl
CH
3 CH c4 135 CI
CH
3 CH N o0 136 CH3 CH o137 Cl CI
CH
3 CH 138
CH
3 CH CF3 139
CF
3
CH
3 CH P 140
CF
3 WO 99/02150 PCT/EP98/04162 - 27 CH 3 CH 141 0 1 N O O1
CH
3 CH o 142
CH
3 CH c 143 aCF 3
CH
3 CH 144
CH
3 CH mo 145
CH
3 CH 146 N02 E/E
CH
3 CH 147 N02 E/Z
CH
3 CH cN 148 .,CF,
CH
3 CH 0> 149
CH
3 CH 150
CH
3 CH 151
CH
3 CH 152
CH
3 CH N153 WO 99/02150 PCT/IEP98/04162 - 28 CH 3 CH 154
CH
3 CH / 155
CH
3 CH - 156
CH
3 CH 157
CH
3 CH 158
CH
3 CH I/ 159
CH
3 CH 160 0
CH
3 CH 161
CH
3 CH 162
CH
3 CH 0 163 Preferred compounds are also those of formula IA4 wherein R I is methyl, X is CH, and A 4 is phenyl, which may be substituted by one or more substituents, selected from hal, lower alkoxy, NO 2 , styryl-phenyl, 5 or (2-CF 3 -, or Cl-phenyl)-furan-2-yl. Such compounds can be prepared according to the procedure set in example 126 (EP-475158 A2 920318), like: (E)-3-Methoxy-2-[2-[(E)-2-[5-(2-trifluoromethyl-phenyl)-furan-2-yl] vinyl]-phenyl]-acrylic acid methyl ester, 10 (E)-2-[2-[(E)-2-(2-chloro-3,4-dimethoxy-6-nitro-phenyl)-vinyl] phenyl]-3-methoxy-acrylic acid methyl ester, WO 99/02150 PCT/EP98/04162 - 29 (E)- 2 -[2-[(E)-2-[5-(2-chloro-phenyl)-furan-2-yl]-vinyl]-phenyl]-3 methoxy-acrylic acid methyl ester and (E)-3-methoxy-2-[2-[(E)-2-[(E)-4-styryl-phenyl]-vinyl]-phenyl] acrylic acid methyl ester. O1Ri RO XN 0 R 4 \ \ A 5 5 IA5
R
1
R
4
A
5 X Expl.No.
NO
2
CH
3 H 2 O- CH 164
O
CH
3 H ci CH 165 CI
CH
3 H CH 166
CH
3 H CH 167 CI C1
CH
3 H CH 168 F F
CH
3 H CH 169 MNI
CH
3 H CH 170
CH
3 H CH 171 WO 99/02150 PCTIEP98/04162 - 30 CH 3 H CH 172
CH
3 H I/ CH 173
CH
3 H / CH 174
CH
3 H CH 175
CH
3 H CH 176
CH
3 H cF, CH 177
CH
3 H F CH 178
CH
3 H CH 179
CH
3 H c CH 180 F
CH
3 H C CH 181
CF
3
CH
3 H CH 182
CH
3 H c, CH 183
CH
3 H P CH 184 Cl
CH
3 H CH 185
CF
3 WO 99/02150 PCT/EP98/04162 -31
CH
3 H CH 186 aF
CH
3 H CH 187 S N
CH
3 H Br CH 188
CH
3 H o CH 189
CH
3 H l CH 190
CH
3 H CH 191
CH
3 H CH 192
CH
3 H CH 193
CH
3 H CH 194
CH
3 H CH 195
CH
3 H CH 196
CH
3 H CH 197
CH
3 H CF3 CH 198
CF
3 WO 99/02150 PCT/EP98/04162 - 32 CH 3 H NCF3 CH 199
CF
3
CH
3 H CH 200
CH
3 H H 201Br
CH
3 H C CH 202 CH3 H 'a c CH 202 Cl
CH
3 H CH 203 Br
CH
3 H 0 H 204
CH
3
CH
3 CH 205
CH
3 H N 206
CF
3 Preferred compounds are also those of formula IA5 wherein R I is methyl, X is CH, R 4 is H and A 5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO 2 , 5 hal, cyano, or CF 3 . Such compounds can be prepared according to the procedure set out in example 164, like: (E)-2-[2-[(lE,3E)-4-(2-Chloro-3,4-dimethoxy-phenyl)-buta-1,3 dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(2-bromo-4,5-dimethoxy-phenyl)-buta-1,3 o10 dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(lE,3E)-4-(2-cyano-phenyl)-buta-1,3-dienyl]-phenyl]-3 methoxy-acrylic acid methyl ester, (E)-3-methoxy-2-[2-[(lE,3E)-4-(3-methoxy-2-nitro-phenyl)-buta-1,3- WO 99/02150 PCTIEP98/04162 - 33 dienyl]-phenyl]-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(4-fluoro-2-trifluoromethyl-phenyl)-buta-1,3 dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(4-tert-butyl-phenyl)-buta-1,3-dienyl]-phenyl] 5 3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(2-chloro-4-fluoro-phenyl)-buta-1,3-dienyl] phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(2,4-difluoro-phenyl)-buta-1,3-dienyl]-phenyl]-3 methoxy-acrylic acid methyl ester, 10 (E)-2-[2-[(1E,3E)-4-(2-chloro-4-methyl-phenyl)-buta-1,3-dienyl] phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(2,4-dimethyl-phenyl)-buta-1,3-dienyl]-phenyl] 3-methoxy-acrylic acid methyl ester and (E)-2-[2-[(1E,3E)-4-(2-fluoro-4-trifluoromethyl-phenyl)-buta-1,3 15 dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester. 0 R' R"O0,XZ 0 IA6
R
1 X A 6 Expl.No.
CH
3 N 207 CF3
CH
3 N cF, 208
CF
3 WO 99/02150 PCTIEP98/041 62 - 34 Ri 0. RI. X 0 0 IA7 RI X A 7 Expl.No.
CIT
3 N 209
CF
3 R~RX R ON 0 N A 8 TAS 5 RlX A 8 Expl.No.
CH
3 CH 210
CF:
3
CH
3 CH )(,CF3 211
CF
3
CH
3 CH '-212 CI CI
CH
3 CH 60213 WO 99/02150 PCT/EP98/04162 - 35 CH 3 CH N 214
CH
3 N 215
CF
3
CH
3 N 216 oq R ' ,X 1O A 9
IA
9
R
1 X A 9 Expl.No.
CH
3 N 217
CF
3 WO 99/02150 PCT/EP98/04162 - 36 0O R'
B
1 s / \ V. IB1
R
I V Bl X Expl.No.
CH
3 -0- CH 218
CH
3 -0- CH 219 Br
CH
3
-N(CH
3 )- CH 220
CH
3
-N(CH
3 )- CH 221
CH
3
-N(CH
3 )- CH 222
CH
3
-N(CH
3 )- CH 223
CH
3 -S- CH 224 1N' WO 99/02150 PCT/EP98/04162 -37 O HR' R .X 0 S O) (CH2)m
B
2 IB2 Rl B 2 X m Expl.No.
CH
3 c CH 1 225
CH
3 CH 0 226 F
CH
3 CH 0 227
CH
3 CH 1 228 Cl
CH
3 CH 1 229
CH
3 CH 1 230
CH
3 CH 1 231 C
CH
3 c CH 1 232
CH
3 q c CH 1 233
CI
WO 99/02150 PCTIEP98/04162 - 38 CH 3 cI CH 0 234 CI
CH
3 CF3 CH 1 235 R X 0 B 0 IB3 Ri B 3 X Expl.No.
CH
3 c CH 236 aCF 3 WO 99/02150 PCT/EP98/04162 - 39 R X 0 0 s / ON B4 0,
R
5 IB4
R
1
R
5
B
4 X Expl.No.
CH
3 0 CH 237
CF
3
CH
3
CH
3 CH 238
CF
3
CH
3
CH
3 CH 239 CH3 H ~~~NCH 240
CH
3 H :)s><CH 240 WO 99/02150 PCT/EP98/04162 - 40 0
,R
l \B5 IB5 Rl B 5 X Expl.No.
CH
3 CH 241
CH
3 - CH 242
CH
3 CH 243 Rl 0 R6 z/ R7 R8 IB 5 Rl Z R 6
R
7
R
8 Expl.No.
CH
3 70@ H H H 244
CH
3
CH
3 H H CH 3 245
CH
3 Br H H H 246
CH
3 H -OCH 3 H H 247 WO 99/02150 PCT/EP98/04162 - 41 CH 3 H H -OCH 3 H 248
CH
3 Cl H H H 249
CH
3 H H H CH 3 250 The activity of the compounds against not only chloroquine resistant, but also chloroquine-sensitive malaria pathogens shows itself in a strong, in vitro measurable growth inhibition of various strains of 5 the human-pathogenic Plasmodium falciparum, as set forth in Table 1 hereinafter. The ratio of the growth inhibition of a strain which is especially resistant to chloroquine and of a strain which is sensitive to chloroquine gives as the "resistance index" a measurement for the absence or presence of a cross-resistance with chloroquine. Since, for all 10 novel compounds the resistance index lies between 0.7 and 2.5, they inhibit the growth of sensitive as well as resistant strains of the malaria pathogen equally effectively. They are accordingly also suitable for the prophylaxis of a malaria disease and also for the treatment of a malaria disease even when chloroquine is ineffective. 15 The good activity against malaria pathogens is also shown in animal experiments. The effective doses measured after oral and subcutaneous administration to mice infected with malaria pathogens are shown in Table 2 hereinafter. Test method for the determination of the activity against 20 Plasmodium falciparum in vitro The preparations are tested on intraerythrocytary stages of Plasmodium falciparum from asynchronous cultures according to the method of Desjardin et al. (Desjardins, R.E. et al: Quantitative assessment of antimalarial activity in vitro by a semiautomated 25 microdilution technique. Antimicrob. Agents Chemother. 16, 710-718, (1979)). The culture medium consists of RPMI 1640 with the addition of 25 mM HEPES, 25 mM NaHCO 3 , 100 gg/ml neomycin and 10% human serum (A+). Human-A+ erythrocytes are used as the Plasmodium WO 99/02150 PCT/EP98/04162 - 42 falciparum host cells. The parasites are maintained at 370C in an atmosphere of 3% 02, 4% CO 2 , 93% N 2 and 95% relative humidity. In order to determine the activity, the preparations are dissolved in DMSO, pre-diluted in the culture medium to a suitable starting 5 concentration and subsequently titrated-out on to microtitre plates in the 2nd stage over 6-7 steps. After the addition of the parasite culture (0.7% parasitemia in 2.5% erythrocyte suspension) the test plates are incubated under the conditions given above for 72 h. The parasite growth in the different preparation concentrations is determined using 10 [G- 3 H]-hypoxanthin incorporation compared to untreated control cultures on the same test plates. The 50% growth inhibition (IC 5 0 ) is calculated according to logit regression analysis from the resulting dosage-activity curve. The preparations are tested on at least one chloroquine-resistant 15 and one chloroquine-sensitive Plasmodium falciparum strain. Additional sensitive and resistant strains are included for futher characterization. Test method for the determination of the activity against Plasmodium berghei in vivo 20 The preparations are tested on mice infected with malaria pathogens (Plasmodium berghei). Male albino mice (IBM:MORO(SPF), FUELLINSDORF) weighing about 25 g are used as the test animals. They are kept in climatized rooms at 21-220C in groups of 5 animals per cage. They receive ad libitum a diet feed with a low PABA content 25 (NAFAG FUTTER " No. 9009 PAB-45, PABA content 45 mg/kg) and drinking water. On the first day of the test (DO) the test animals are infected with Plasmodium berghei (strain ANKA). For this there is used heparinized blood of a donor mouse with about 30% parasitemia, which is diluted with physiological saline such that it contains 108 30 parasitized erythrocytes per ml. 0.2 ml of this suspension is injected intravenously (i.v.) into the mice to be treated and into the control mice. In untreated control animals the parasitemia normally reaches 30-40% on the third day after the infection (D+3) and the test animals die between days +5 and +7.
WO 99/02150 PCT/EP98/04162 -43 The substances to be tested are dissolved or suspended in distilled water or in a mixture of 7% Tween 80, 3% alcohol (96%) and water. Usually, 0.25 ml of this solution or suspension is administered once subcutaneously and perorally to groups of 5 test animals. Treatment is 5 effected 24 hours after the infection. 10 control animals are treated in the same manner with solvent or suspension medium per test. All substances are tested in a first test in a single dosage of 100 or 10 mg/kg. Only those substances which in this test (10 mg/kg) have shown a parasitaemia reduction of more than 90% are used for the 10 titration. Suitable dilutions of the test substance can be used to obtain an accurate titration of the activity. 48 hours after the treatment (D+3) blood smears are prepared from all animals using blood from tail veins and are stained with giemsa. The average erythrocyte infection rate (parasitemiea in %) in 15 the control groups as well as in the groups which have been treated with the test compounds is determined by counting under a microscope. The difference in the average values of the infection rates of control group (100%) and treated groups is calculated and expressed as a percentage reduction (GI%). The ED 5 o or ED 9 0 is determined 20 mathematically by means of the JMP programme (nonlinear fit). The
ED
50 (EDgo 9 0 ) in mg/kg is that dose which after single administration reduces the average erythrocyte infection rate by 50% (90%) in comparison to the control group.
WO 99/02150 PCT/EP98/04162 - 44 Table 1 Values measured in vitro (ICso values in pg/ml) for the grouth inhibition of the human-pathogenic Plasmodium falciparum strain NF54 as an example of a chloroquine-sensitive strain and of the 5 human-pathogenic Plasmodium flaciparum K1 as an example of a chloroquine-resistant strain. Formula Example No. in vitro strain NF 54 strain K1
IC
50 72 h IC 50 72 h IAl 11 1.17 4.9 IAl 28 17.7 19.1 IA2 105 0.21 1.01 IA2 110 20 65.8 IA2 111 1.6 4.3 IA3 120 1.75 2.51 IA4 126 1.2 3.3 IA4 136 1.04 2.9 IA5 185 0.06 0.15 IA5 199 0.06 0.13 IA5 203 0.07 0.28 IA5 206 0.4 1.4 IA6 207 10.8 25.8 IA7 209 3.21 5.7 IA8 210 0.85 1.35 WO 99/02150 PCT/EP98/04162 - 45 IA8 211 0.33 1.34 IA9 217 23.7 60.8 IB1 222 22,6 64.3 IB4 238 17.5 40.9 IB5 241 1.4 7.4 IB5 243 6.7 22.6 IB 244 147.3 419.2 IB 250 184.4 550.3 IB2 233 29.5 67.3 IB3 236 44.2 174.7 III 251 64.9 111 Table 2 Activity measured in vivo against Plasmodium berghei in mice in percentage reduction of the parasitemia after a perorally (po) or 5 subcutaneously (sc) administered dose of 100 (10) mg/kg of test substance, ED 50 is the effective administered dose of test substance Formula Example No. in vivo po act. % sc act. % IAl 11 80 tox IA3 120 46 91 IA4 126 79 76 IA4 136 40 tox WO 99/02150 PCTIEP98/04162 - 46 IA5 185 99.0 (10 mg/kg) 99.95 IA5 199 100 (10 mg/kg) 99.97 IA5 203 76 (10 mg/kg) 90 IA5 206 46 44 IA8 210 82 99 IA8 211 59 (10 mg/kg) 92 III 251 40 74 The compounds of formula IA or IB and the pharmaceutically acceptable acid addition salts of the compounds of formula IA or IB can be used as medicaments, e.g. in the form of pharmaceutical 5 preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, drag6es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions, or 10 nasally. The compounds of formula IA or IB and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or 15 derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, drag6es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient 20 no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
WO 99/02150 PCTIEP98/04162 - 47 The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still 5 other therapeutically valuable substances. Medicaments containing a compound of formula IA or IB or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their manufacture which comprises bringing one or 10 more compounds of formula IA or IB and/or pharmaceutically acceptable acid addition salts thereof into a galenical administration form together with one or more therapeutically inert carriers. In accordance with the invention compounds of general formula IA or IB as well as their pharmaceutically acceptable acid addition salts 15 can be used for the treatment or prevention of malaria and, respectively, for the production of corresponding medicaments. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in a range of about 10 mg to about 2.5 g 20 per day of a compound of general formula IA or IB or the corresponding amount of a pharmaceutically acceptable acid addition salt thereof, although the upper limit can also be exceeded when this is found to be indicated. In the following Examples, which illustrate the present invention 25 but are not intended to limit its scope in any manner, all temperatures are given in degrees Celsius. The 250 MHz- 1 H-NMR spectra were measured at room temperature; chemical shifts 8(ppm) relative to 5(TMS) = 0.0 ppm. The novel compounds of formula IA5 can be prepared as described 30 below. All temperature are given in 'C.
WO 99/02150 PCT/EP98/04162 -48 Example 164 (E)-2- [2-(1E,3E)-4-[4,5-Dimethoxy-2-nitro-phenyl)-buta-1,3-dienyl] phenvL1]-3-methoxy-acrvylic acid methyl ester a) At room temperature, NaOCH 3 (335 mg, 6.19 mmol) was added to 5 a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C. Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 500 for overnight, the mixture was poured over water, and extracted with 10 ether, washed with brine and dried over MgSO 4 . The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2N HC1 (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room 15 temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5 dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105'. IR (KBr): 1689, 1605 cm -1 . MS (EI): 237 (M). b) At 00, NaH (40 mg, 0.954 mmol) was added to a solution of (E)-2 [2-(dimethoxy-phosphorylmethyl)-phenyl]l-3-methoxy-acrylic acid 20 methyl ester (EP-203606) (250 mg, 0.79 mmol) in THF (5 ml). The mixture was stirred at room temperature for 30 min and treated with (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (189 mg, 0.79 mmol) in
CH
2 C1 2 (2 ml). After the mixture was stirred at room temperature for 3 h and refluxed for 1.5 h, the reaction mixture was cooled to room 25 temperature and treated with CH 3
CO
2 H (1 ml). After stirring for 10 min at room temperature, the reaction mixture was extracted with ethylacetate, washed with NaHCO 3 solution, brine, water, and dried over MgSO 4 . Evaporation of the solvent and chromatography (hexane/ethylacetate 1:1) gave (E)-2-[2-(1E,3E)-4-[4,5-dimethoxy-2 30 nitro-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester (116 mg, 34%) as white solid, m.p. 198-200'. IR (KBr): 1710, 1630 cm -1 . MS (EI): 425 (M). According to the procedure set forth in the preceding example, the following compounds were prepared: WO 99/02150 PCT/EP98/04162 - 49 Example 165 (E)-2-[2-[(1E,3E)-4-(2,4-Dichloro-phenvl)-buta-1,3-dienyll-phenvl1-3 methoxy-acrylic acid methyl ester m.p. 143-145' 5 IR (KBr): 1707, 1629 cm -1 , MS (EI): 388 (M). Example 166 Methyl (E and/or Z)-3-methoxy-2-[o-[(all-E)-4-(2-pyridyl)-1,3 butadienv1l phenv1] acrvlate m.p. 106-108' 10 Example 167 Methyl (E and/or Z)-2-fo-[(all-E)-4-(2,3-dichlorophenvyl)-1,3-butadienyll phenvll-3-methoxvacrylate m.p. 141-145' Example 168 15 Methyl (E and/or Z)-2-[o-[(all-E)-4-(2,3-difluorophenvyl)-1,3-butadienyl] phenll-3-methoxyacrylate m.p. 142-144' Example 169 Methyl (E and/or Z)-3-methoxv-2-fo-[(all-E)-4-(2-quinolinvl)-1,3 20 butadienyllphenvl1acrylate m.p. 137-138' Example 170 Methyl (E and/or Z)-3-methoxy-2-[o-[(all-E)-4-(1-naphthvl)-1,3 butadienyll phenyl acrvylate 25 m.p. 138-140' WO 99/02150 PCT/1EP98/04162 - 50 Example 171 Methyl (E and/or Z)-3-methoxv-2-[0- [(all-E)-4-( 1-methylpyvrrol-2-yl)- 1,3 butadienyll phenyl] acryiate m.p. 139-142' 5 Example 172 Methyl (E and/or Z)-3-methoxy-2- ro-r( all-E)-4-(4-lpyridyl)- 1.3 butadienyl] phenyl] acri~yate m.p. 175-177' Example 173 10 Methyl (E and/or Z)-2- [o- [(all-E)-4-(2-furyl)- 1.3-butadienyll ~henyl] -3 methoxyacrylate m.p. 136-137' Example 174 Methyl (E and/or Z)-3-methoxv-2- ro- [(all-E)-4-(2-thienyl)- 1.3 15 butadienyl] phenyl] acryiate m.p. 142-145' Example 175 Methyl (E and/or Z)-3-methoxy-2- ro-[(all-E and/or Z)-4-(3-thienyl)- 1.3 butadienyll -phenyll acvLate 20 m.p. 194-195' Example 176 Methyl (E and/or Z)-3-methoxy-2- fo- [(all-E)-4-( 3-puinolinlyl)- 1.3 butadienyl] phenyll -3-methoxcyacrylate m.p. 173-175* WO 99/02150 PCTIEP98/04162 - 51 Example 177 Methyl (E)-3-methoxv-2- ro- [(all-E)-4-(alpha,alp~ha, al-pha-trifluoro-p) tolyl)-1,3-butadienyllphenyl] acrvlate M.P. 190-191' 5 Example 178 Methyl (E)-2- [o-[(all-E)-4-(p3-fluoro-phenyl)- 1 3-butadienvi] phenl -3 methoxvyaclylate m.p. 156-157' Example 179 10 Methyl (E)-2-[a- [(all-E)-4-(o-ethoxyphenyl)-1 .3-butadienylliphenyll -3 methoxyacrylate m.p. 152-153' Example 180 Methyl (E)-2- ro- [(all-E)-4-(2-chloro-6-fluorop~heniyl)- 1,3 15 butadienyliphenyl] acrvLate m.p. 1650 Example 181 Methyl (E )-3-methoxy-2- fo-[(all-E)-4-( al-pha~alp~ha. alpha-trifluoro-m tolyl)- 1 3-butadienyll-phenl acrylate 20 m.p. 152-153' Example 182 Methyl (E)-2- ro- [(all-E)-4-( 3-furyl)- 1 3-butadienyll uhenvi] -3 methoxyacr~ylate m.p. 174-175' WO 99/02150 PCTIEP98/041 62 - 52 Exami~1e 183 Methyl (E )-2- ro- r(all-E)-4- r2-(P-chloro-phenyl)-4-thiazolyl] -1.3 butadienyl] phenyll -3-methoxyacryl ate m.p. 167-171' 5 Example 184 Methyl (E )-2- ro- [(all-E)-4-(o-chloro-phenyl)- 1.3 butadienyl] phenil acryiate m.p. 158-162' Example 185 10 Methyl (E )-3-methoxy-2- ro- [(all-E)-4-( alpha~alp~ha~alpha-trifluoro-tolyl) 1. 3-butadienyli] henvi] acrylate m.p. 148-149' Example 186 Methyl (E)-2- 14 r(all-E)-4-(m-fluorop~henyl)- 1 3-butadienylI phenvil -3 15 methox;yacr~ylate JR (KBr): 1705, 1628 cm-1, MS (El): 338 (M) Example 187 Methyl (E)-3-methoxvy-2- ro- r(all-E)-4-( 5-phenyl-4-thiazolvl)- 1.3 butadienyl] phenvi] acrvl ate 20 m.p. 1670 Example 188 Methyl (E )-2- ro- (all-E)-4-(5-bromo-2-thienyl)- 1 3-butadienyll uhenvi] -3 methoxcyacrylate m.p. 160-161' WO 99/02150 PCTIEP98/04162 - 53 Example 189 Methyl (E)-3-methoxy-2- [0- Rall-E)-4-(p)-methoxvphenyl)- 1 3-butadienyll phenyl] acrvylate m.p. 164-166' 5 Example 190 Methyl (E)-3-methoxy-2- fo- [(all-E)-4- [3-methoxybenzo fbithiophen-2-yl] 1 .3-butadienyl] phenyl] acrylate m.p. 202-203' Example 191 10 Methyl (E)-3-methoxy-2- o[ (all-E)-3-(2-thiazolyl)-1,3 butadienayll phenyll acrvi ate m.p. 131-133* Example 192 Methyl (E)-3-methoxy-2- o[ (all-E)-4-( 5-methyl-2-thienyl)- 1.3 15 butadienyli pheniyl] acrylate m.p. 131-133* Example 193 Methyl (E)-3-methoxy-2- fo-F( all-E)-4-(3-methyl-2-thienyl)- 1.3 butadienyll phenyl] acrylate 20 m.p. 1680 Example 194 Methyl (E)-3-methoxy-2- Fo- F4-( 2-na-phthyl)- 1.3 butadienyll phenyl] acryl ate m.p. 1720 WO 99/02150 PCT/EP98/04162 - 54 Example 195 Methyl (E)-2- [o- [(all-E)-4-benzo [bthiophen-2-vl-1,3-butadienyl]phenyl 3-methoxy-acrylate m.p. 223-225' 5 Example 196 Methyl (E)-2-[o-[(all-E)-4-benzo [b]thiophen-3-vl-1,3-butadienyl]phenyll 3-methoxy-acr1ylate m.p. 1570 Example 197 10 Methyl (E)-3-methoxy-2-ro-[(all-E)-4-phenvyl-1,3 butadien11phenyv1l acrylate m.p. 165-167' Example 198 (E)- or (Z)-2- [2- [4-(3,5-bis-trifluoromethy1-phenyl)-buta-1,3 15 dienvl]phen1y-3-methoxy-acrylic acid methyl ester IR (KBr): 1703, 1630 cm -1 MS (EI): 456 (M) Example 199 (E)- or (Z)-2-[2-[4-(2,4-bis-trifluoromethyl-phenyl)-buta-1,3 20 dienvllphen1]-3-methoxy-acrylic acid methyl ester m.p. 176-177' IR (KBr): 1703, 1630 cm- 1 MS (EI): 456 (M) WO 99/02150 PCT/EP98/04162 - 55 Example 200 Methyl-2-[o-[(all-E)-4-(m-bromophenyl)-1,3-butadienyllphenv11-3 methoxvacrylic IR (KBr): 1701, 1626 cm- 1 5 MS (EI): 399 (M) Example 201 Methyl (E)-2-[o-[(all-E)-4-(p-chlorophenyl)-1,3-butadienvyl]phenvl-3 methoxyacrylate m.p. 2090 0lo Example 202 Methyl (E)-2-fo-[(all-E)-4-(m-chlorophenyl)-1,3-butadienylphenyl]-3 methoxvacrvlate m.p. 121-122o Example 203 15 Methyl (E)-2-[o-[(all-E)-4-(o-bromophenvl)-1,3-butadienyllphenvl]-3 methoxvacrvlate m.p. 150-151' Example 204 Methyl (E)-3-methoxy-2- [o- [(all-E)-4-(3,4,5-trimethoxyphen1yl)-1,3 20 butadienyllphenvylacrvlate m.p. 98-1020 Example 205 Methyl (E)-2-[o-[(all-E)-4-(p-tert-butylphenyl)-3-methyl-1,3-butadienyl phenyl] 3-methoxvacrvlate 25 IR (KBr): 1709, 1632 cm- 1 MS (EI): 390 (M) WO 99/02150 PCT/EP98/04162 -56 Example 206 (Z)- or (E)-Methoxvimino-[2-[(lE,2E)-4-(2-trifluoromethylphenyl)-buta 1,3-dienvyl]-phenyll -acetic acid methyl ester a) At 24o, Bu 3 SnH (0.56 ml, 2.1 mmol) was added to a solution of 5 (2-ethynyl-phenyl)-methoxyimino-acetic acid methyl ester (151 mg, 0.7 mmol) and AIBN (cat.) in toluene (0.5 ml). After the mixture was stirred at 800 for 3.5 h, solvent was evaporated under reduced pressure and chromatography (hexane/ethylacetate 9:1) gave methoxyimino-[2-(E,Z) (2-tributylstannanyl-vinyl)-phenyl]-acetic acid methyl ester (1:1 10 mixture) (155 mg, 44%) as a yellowish liquid. IR (KBr): 1731, 1600 cm- 1 . MS (EI): 508 (M). b) A solution of 1-(2,2-dibromo-vinyl)-2-trifluoromethyl-benzene (989 mg, 3 mmol), and (Et) 2 POH (0.75 ml, 6 mmol) in Et 3 N (0.83 ml, 6 mmol) was stirred at 50 for 4 h. Hexane was added, and stirred for 15 further 10 min. The mixture was extracted with hexane, washed with brine and dried over Na 2
SO
4 . Evaporation of the solvent and chromatography (hexane) gave 1-(2-bromo-vinyl)-2-trifluoromethyl benzene (674 mg, 90%) as a colorless liquid. IR (KBr): 1600, 940 cm- 1 . MS (EI): 251 (M). 20 c) At 240, Pd[PPh 3
]
4 (21 mg, 0.02 mmol) was added to a solution of 1 (1-bromo-vinyl)-2-trifluoromethyl-benzene (151 mg, 0.6 mmol) and methoxyimino- [2-(E,Z)-(2-tributylstannanyl-vinyl)-phenyl]-acetic acid methyl ester (304 mg, 0.6 mmol) in toluene (5 ml). The mixture was stirred at 1100 for 5 h, cooled to room temperature, extracted with 25 toluene, washed with brine, and dried over Na2SO 4 . Evaporation of the solvent and chromatography (hexane/ ethylacetate 3:2) gave (Z)- or (E) methoxyimino-[2-[(lE,2E)-4-(2-trifluoromethylphenyl)-buta-1,3-dienyl] phenyll-acetic acid methyl ester (48 mg, 21%) as brown oil. IR (KBr): 1734, 1610 cm- 1 . MS (EI): 389 (M).
WO 99/02150 PCT/EP98/04162 - 57 Example 251 (III) (E)-3-Methoxy-2-((E)-2-[(R)- and (S)-3-(tetrahvdro-pvran-2-vloxy} propenyll-phenyl-acrylic acid methyl ester (active intermediate) At 24', Pd[PPh 3
]
4 (58 mg, 0.05 mmol) was added to a solution of 5 (E)-tributyl-[3-(R)- and (S)-(tetrahydro-pyran-2-yloxy)-propenyl] stannane (2.2 g, 5.1 mmol) (E.J. Corey; J.W. Suggs, J. Org. Chem. 40, 2554, (1975)) and (E)-2-(2-bromo-phenyl)-3-methoxy-acrylic acid methyl ester (1.38 mg, 5.1 mmol) (EP 0307101 A2 890315) in toluene (20 ml). The mixture was stirred at 1100 for 2 days, cooled to room temperature, 10 extracted with toluene, washed with brine, and dried over Na 2
SO
4 . Evaporation of the solvent and chromatography (hexane/ethylacetate 9:1) gave (E)-3-methoxy-2-[(E)-2-[(R)- and (S)-3-(tetrahydro-pyran-2 yloxy)-propenyl]-phenyl]-acrylic acid methyl ester (884 mg, 52%) as a white solid, m.p. 66-68'. IR (KBr): 1711, 1633 cm -1 . MS (EI): 216 (M 15 MeOH-Dihydropyrane). Example 252 (IV) (E)-2-[2-(3-Hydroxy-propenyl)-phenyll-3-methoxy-acrylic acid methyl ester (active intermediate) At 240, toluene-4-sulfonic acid monohydrate (1.11 g, 0.4 mmol) was 20 added to a solution of (E)-3-methoxy-2-[(E)-2-[(R)- and (S)-3-(tetrahydro pyran-2-yloxy)-propenyl]-phenyl]-acrylic acid methyl ester (4.866 g, 14 mmol) in ethanol (70 ml). After the mixture was stirred for 6 h and neutralized with K 2
CO
3 solution, the solvent was evaporated and the crude was dissolved in ethylacetate, washed with brine, water, and 25 dried over Na 2
SO
4 . Evaporation of the solvent gave (E)-2-[2-(3-hydroxy propenyl)-phenyl]-3-methoxy-acrylic acid methyl ester (3.4 g, 93%) as a white solid, m.p. 78-80'. IR (KBr): 1683, 1619 cm -1 . MS (EI): 216 (M MeOH). Example A 30 (E)-2-[2-(1E,3E)-4- [4,5-Dimethoxy-2-nitro-phenyl)-buta-1,3-dienyl] phenyl]-3-methoxyacrylic acid methyl ester can be formulated as the active ingredient according to methods known per se to give pharmaceutical preparations of the following composition: WO 99/02150 PCTIEP98/04162 - 58 1. 500 mg tablets Active ingredient 500 mg Powd. lactose 149 mg Polyvinylpyrrolidone 15 mg 5 Dioctyl sodium sulphosuccinate 1 mg Na carboxymethylstarch 30 mg Magnesium stearate 5 mg 700 mg 2. 50 mg tablets 10 Active ingredient 50 mg Powd. lactose 50 mg Microcrystalline cellulose 82 mg Na carboxymethylstarch 15 mg 200 mg 15 3. 100 mg capsules Active ingredient 100.0 mg Powd. lactose 104.7 mg Corn starch 70.0 mg Hydroxypropylmethylcellulose 10.0 mg 20 Dioctyl sodium sulphosuccinate 0.3 mg Talc 12.0 mg Magnesium stearate 3.0 mg 300.0 mg 4. 500 mg suppositories 25 Active ingredient 500 mg Suppository mass ad 2000 mg 5. 100 mg soft gelatine capsules Active ingredient 100 mg Medium chain triglyceride 300 mg 30 400 mg

Claims (18)

1. The use of compounds of formulae IA or IB 0 R1.I .- O 0 R 1 RI o- O R1 R 1 R0,X O R" R or Z I S IA R 7 R8 IB wherein 5 R 1 is lower alkyl X is N or CH A' R in IA is Y lal wherein Y is S or O and 10 A 1 is phenyl, which may be substituted by one or more substituents, selected from halogen, lower alkoxy, lower alkyl, CF 3 , NO 2 , NH 2 , phenoxy or CF 3 phenoxy; naphthyl; isothiazol-3-yl; thiazol-2-yl, optionally substituted by lower alkoxyalkoxyalkyl, 15 lower alkyl, lower alkoxycarbonyl or lower acetoxyalkyl; thiadiazol-2-yl, optionally substituted by lower alkylthio, lower alkinylthio, cycloalkyl alkylthio, CF 3 or -NHC 6 H 4 CF 3 ; quinoxalin-2-yl, optionally substituted by halogen or lower alkyl; 20 benzoxazol-2-yl; benzotriazine, optionally substituted by an oxo-group; and quinolin-2-yl; N A 2 or 2 Ia2 wherein R 2 is hydrogen, lower alkoxycarbonyl, CF 3 , lower 25 alkyl, cycloalkyl, lower alkoxyalkyl, lower alkylthioalkyl or lower alkoxy and WO 99/02150 PCTIEP98/04162 - 60 A 2 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, CF 3 , halogen, lower alkylthio, lower alkoxy or NO 2 ; -C(O)C 6 H 5 ; -C(CH 3 )=CH-C 6 H 4 -lower alkyl; 5 -CH=CH-C 6 H 5 ; pyridin-2-yl; pyridin-3-yl; pyridin
4-yl; thiazol-5-yl, optionally substituted by lower alkyl; thien-3-yl, optionally substituted by lower alkyl; thien-2-yl, optionally substituted by halogen; quinolin-2-yl; naphthyl, 10 benzo[b]thiophen-2-yl, optionally substituted by lower alkyl or halogen; or benzo[b]furan-2-yl; R 3 or ' W 1 a3 wherein W is S, O, NH or CH 2 ; 15 R 3 is hydrogen or lower alkyl and A 3 is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H pyran or phenyl, which may be substituted by one or more substituents, selected from halogen, CF 3 or lower alkyl; A A4 20 or A Ia4 wherein A 4 is phenyl, which may be substituted by one or more substituents, selected from NO 2 , lower alkoxy, halogen, CF 3 , phenyloxy, styryl-phenyl or 25 (2-CF 3 - or Cl-phenyl)-furan-2-yl; benzo[1,3]dioxol
5-yl, optionally substituted by halogen; isoxazol-4 yl, optionally substituted by phenyl or lower alkoxyalkoxy; quinolin-3-yl; pyridin-2-yl; pyridin 3-yl, pyridin-4-yl; furyl; thien-2-yl; thien-3-yl; 30 C=-C-C(CH 3 )3; -C-C-C 6 H5; indolizin-2-yl, optionally substituted by lower alkyl; benzofuran 2-yl; benzopyran-3-yl or dihydrobenzo [b] thiophen 5-yl; R 4 or A 5 Ia5 WO 99/02150 PCT/EP98/04162 -61 wherein R 4 is hydrogen or lower alkyl; and A 5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower 5 alkoxy, NO 2 , halogen, cyano or CF 3 ; pyridin-2-yl; pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower alkyl; 10 thiazol-2-yl, optionally substituted by C 6 H 4 C1; thiazol-4-yl, optionally substituted by phenyl; benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo[b]thiophen-3-yl; or Ia6 15 wherein A 6 is phenyl, optionally substituted by CF 3 ; or A 7 Ia7 wherein A 7 is phenyl, optionally substituted by CF 3 ; 20 or -(CH 2 )n-A 8 la8 wherein n is 4 and A 8 is phenyl, which may be substituted by one or more substituents, selected from CF 3 , halogen or 25 -CH=N-OCH 2 -CO-OCH 3 ; naphthyl or pyridin-4-yl; S or A-C A 9 Ia9 or wherein A 9 is phenyl, optionally substituted by CF 3 ; and wherein in formula IB 30 R 6 -R 8 are hydrogen, lower alkyl or lower alkoxy and Z is hydrogen; lower alkoxy; lower alkyl; or halogen or v IbI wherein WO 99/02150 PCT/EP98/04162 - 62 V is O, -N(CH 3 )-, -S- and B 1 is phenyl, optionally substituted by halogen or alkyl; quinolin-8-yl; pyrimidin-2-yl; -CH(CH 3 ) C 6 H 5 ; or -CH 2 -C 6 H 5 ; o O , (CH2)m B2 5Or 2 wherein m is 0 or 1; and B 2 is phenyl, optionally substituted by halogen, lower alkyl or CF 3 ; or benzo[b]thiophen-5-yl; O 10 or 0 B 3 Ib3 wherein B 3 is phenyl, optionally substituted by CF 3 ; 0.N Z B 4 orR5 Ib4 or wherein 15 R 5 is hydrogen, lower alkyl or lower alkoxyalkyl and B 4 is phenyl, optionally substituted by CF 3 ; pyridin 2-yl; or thiazolin-5-yl, optionally substituted by lower alkyl; or B Ib5 20 wherein B 5 is phenyl; -C=C-C(CH 3 ) 3 ; or thien-3-yl; as well as pharmaceutically acceptable salts and possible stereoisomers as well as their racemates of compounds of formulae IA and IB as therapeutically active substances. 25 2. The use according to claim 1 against chloroquine-sensitive and chloroquine-resistant pathogens and respectively, for the production of corresponding medicaments. 3. The use according to claims 1 to 2 of compounds of formula IA from the group of compounds WO 99/02150 PCT/EP98/04162 - 63 R 1 O X R'A' \-Y RON . 0 IA1l wherein R 1 , X, Y and A 1 have the significances given in claim 1. 4. The use according to claims 1 and 2 of compounds of formula IA 5 from the group of compounds O 0 /R 2 *N. oN A 2 IA2 wherein R 1 , X, R 2 and A 2 have the significances given in claim 1. 5. The use according to claims 1 and 2 of compounds of formula IA 10 from the group of compounds RO 1 SN 0 R 3 \ w IA3 wherein R 1 , X, R 3 , W and A 3 have the significances given in claim 1.
6. The use according to claims 1 and 2 of compounds of formula IA 15 from the group of compounds WO 99/02150 PCTIEP98/04162 - 64 RR X R N0 - - 0 \ A 4 IA4 wherein R 1 , X and A 4 have the significances given in claim 1.
7. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds ORR 1 R'A X RO X 0 R 4 \- \ As 5 IA5 wherein R 1 , X, R 4 and R 5 have the significances given in claim 1.
8. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds 0 N 0 R.oOX Ro 10 IA6 wherein R 1 , X and A 6 have the significances given in claim 1.
9. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds WO 99/02150 PCT/EP98/04162 - 65 R 1 0 R X o A 7 IA7 wherein R 1 , X and A 7 have the significances given in claim 1.
10. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds R 1 O/ < 0 0 R O,. X1 0 A 8 5 IA8 wherein R 1 , X, n and A 8 have the significances given in claim 1.
11. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds 0 OOR' I R O. 1 O S A9 10 IA9 wherein R 1 . X and A 9 have the significances given in claim 1.
12. The use according to claims 1 and 2 of compounds of formula IB from the group WO 99/02150 PCT/EP98/04162 - 66 O R 1 R ~o.Xo R X B 1 IB1 wherein R 1 , X, V and B 1 have the significances given in claim 1.
13. The use according to claims 1 and 2 of compounds of formula 5 IB from the group oR 1 0 O k(CH)m 2 y IB2 wherein R 1 , X, m and B 1 have the significances given in claim 1.
14. The use according to claims 1 and 2 of compounds of formula 10 IB from the group 00 R1 POO 0 lo -1 0 0 O/ 0'< B3 IB3 wherein R 1 , X and B 3 have the significances given in claim 1.
15. The use according to claims 1 and 2 of compounds of formula IB from the group WO 99/02150 PCT/EP98/04162 - 67 0 o R 1 x 0'N B 4 IB4 wherein R 1 , X, R 5 and B 4 have the significances given in claim 1.
16. The use according to claims 1 and 2 of compounds of formula 5 IB from the group O R 1 R ., O 0 RNo"X0 \ B 5 S IB5 wherein R 1 , X and B 5 have the significances given in claim 1.
17. The use according to claims 1 and 2 of compounds of formula IB, wherein R 6 , R 7 and R 8 have the significances given in claim 1 and Z 10 is lower alkoxy, lower alkyl, halogen or hydrogen.
18. Compounds of formula R0 X O 0 R 4 N. 5 \ \ As /" IA5 wherein R 1 is lower alkyl, 15 X is N orCH, R 4 is hydrogen or lower alkyl and WO 99/02150 PCTIEP98/04162 - 68 A 5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO 2 , halogen, cyano or CF 3 ; pyridin-2-yl; pyridin-4-yl; quinolin-2 yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally 5 substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower alkyl; thiazol-2-yl, optionally substituted by C 6 H 4 C1; thiazol-4-yl, optionally substituted by phenyl; benzo[b]thiophen-2-yl, optionally substituted by halogen; or 10 benzo[b]thiophen-3-yl; as well as their pharmaceutically acceptable salts and possible stereo isomers as well as their racemates.
19. A medicament, especially for the treatment and/or prevention of malaria, containing one or more compounds according to any one of 15 claims 1-16 and at least one therapeutically inert excipient.
20. The invention as hereinbefore described.
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